Sparsentan Use Could Lower Risk of Kidney Failure, Death in FSGS

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Although the DUPLEX trial missed its primary endpoint of eGFR slope in patients with FSGS, results point to greater reductions in proteinuria and in risk of kidney failure with sparsentan use relative to irbesartan—making its case for becoming a standard of care for the glomerular disease.

Michelle Rheault, MD | Credit: University of Minnesota

Michelle Rheault, MD
Credit: University of Minnesota

Use of sparsentan resulted in greater reductions in proteinuria than irbesartan but did not contribute to a between-group group in estimated glomerular filtration rate (eGFR) slope among patients with focal segmental glomerulosclerosis (FSGS), according to results of the phase 3 DUPLEX trial.

A 371-person trial comparing sparsentan against irbesartan in patients with FSGS for 108 weeks, results indicate the trial failed to meet its primary efficacy endpoint of change in eGFR slope at the time of final analysis relative to irbesartan, but investigators noted exploratory analyses pointed to a trend towards lower risk of adverse kidney outcomes, including kidney failure and renal death.1

“To be able to tell [patients] here: ‘I have this drug that has almost a 20% chance of putting them into complete remission’. I think most patients would jump at that, especially given this the safety profile that we're seeing,” explained principal investigator Michelle Rheault, MD, a pediatric nephrologist and professor of pediatrics at the University of Minnesota, during a press conference at the American Society of Nephrology Kidney Week 2023.

A dual endothelin type A and angiotensin II type 1 receptor antagonist, sparsentan was the subject of the phase 2 DUET trial, which concluded sparsentan-treated patients had greater reductions in urinary protein-to-creatinine ratio and a greater rate of FSGS partial remission than irbesartan-treated patients after 8 weeks of treatment.2 Based on the results of this trial, Travere Therapeutics funded the phase 3 DUPLEX trial, which was launched in 2017.1

A multicenter, double-blind, active-controlled trial, DUPLEX enrolled patients aged 8 to 75 years, with biopsy-confirmed FSGS or a documented pathogenic variant in a podocyte protein associated with FSGS, a urinary protein-to-creatinine ratio of 1.5 or greater, and an eGFR of at least 30 mL/min/1.73m2 of body-surface area at screening.1

Withs screening for eligibility occurring from April 17, 2018, and January 5, 2021, investigators identified 371 who underwent subsequent randomization in a 1:1 ratio, with 184 randomized to sparsentan and 187 randomized to irbesartan. According to investigators, the trial arms were stratified according to eGFR and both arms were well balanced. Of note, children and adolescents made up 9.4% of the study population.1

The trial was designed with a prespecified interim analysis at 36 weeks, which used a surrogate efficacy endpoint of FSGS partial remission of proteinuria, which was defined as a urinary protein-to-creatinine ratio of 1.5 or less and a 40% or greater reduction in the ratio from baseline. The primary efficacy endpoint was the eGFR slope at the time of the final analysis.1

Investigators assessed change in eGFR from baseline to 4 weeks after the end of treatments as a secondary endpoint. Investigators also pointed out the intention to assess a composite kidney outcome of a confirmed reduction in eGFR of at least 40%, kidney failure, or death in an exploratory analysis.1

At 36 weeks, analysis of the surrogate efficacy endpoint suggested partial remission of FSGS was achieved in 42.0% of the sparsentan group and 26.0% of the irbesartan group (P =.009). Further analysis indicated this response was sustained throughout the 108-week duration of the trial.1

At 108 weeks, the following results were observed:1

  • No significant between-group differences in the eGFR slope
  • A between-group difference in total slope of 0.3 mL/min/1.73m2 (95% confidence interval [CI], −1.7 to 2.4)
  • A between-group difference in the slope from week 6 to week 108 of 0.9 mL/min/1.73m2 per year (95% CI, −1.3 to 3.0)

Analysis of the primary efficacy endpoint detailed mean changes in eGFR from baseline to week 112 of -10.4 mL/min/1.73m2 with sparsentan and -12.1 mL/min/1.73m2 with irbesartan (difference, 1.8 mL/min/1.73m2; 95% CI, -1.4 to 4.9). Assessment of the composite kidney outcome suggested such an event occurred among 20.1% of the sparsentan group and 23.0% of the irbesartan group (Relative risk [RR], 0.87; 95% CI, 0.60 to 1.26). Additional analysis assessing the individual components of the composite outcome suggested kidney failure occurred among 6.5% and 11.2% of the sparsentan and irbesartan groups, respectively (RR, 0.58; 95% CI, 0.31 to 1.07).1

Investigators highlighted similar safety profiles between the study agents, which was supported by a similar frequency of adverse events observed in the trial.1

In an editorial published in the New England Journal of Medicine, Julie R. Ingelfinger, MD, pediatrician and senior consultant in Pediatric Nephrology at Massachusetts General Hospital, commended the investigators of this trial for their efforts and findings, but also noted it leaves numerous questions around the progression of FSGS and the potential role of sparsentan.3

“In the end, does sparsentan offer another arrow in the small quiver of armaments with which to treat FSGS? It is a start, and one hopes that further observation of the trial participants in the ongoing open-label extension, plus additional studies aimed at answering the many questions the trial raises, will provide an answer,” Ingelfinger wrote.3

References:

  1. Rheault MN, Alpers CE, Barratt J, et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. New England Journal of Medicine. Published online November 3, 2023. doi: 10.1056/NEJMoa2308550
  2. Trachtman H, Nelson P, Adler S, et al. DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS [published correction appears in J Am Soc Nephrol. 2019 Mar;30(3):518]. J Am Soc Nephrol. 2018;29(11):2745-2754. doi:10.1681/ASN.2018010091
  3. Ingelfinger JR. Sparsentan — Another Arrow in the Quiver for Treatment of FSGS?New England Journal of Medicine. Published online November 3, 2023. doi: 10.1056/NEJMe2312324
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